The role of disrupted gut mucosal homeostasis in cardiometabolic disease

Diet explains almost half of the cardiometabolic disease (CMD) burden. Notably, low fiber intake increases CMD risk, although fibers cannot be digested by human enzymes. Instead, fibers are a key energy source for beneficial gut bacteria.

Our symbiotic relationship with the gut microbiota is dependent on their separation from intestinal cells through a barrier of secreted mucus. However, the mucus also provides nutrition for its own distinct niche of bacteria.

In mice, fiber deprivation leads to expansion and disruption of this niche, resulting in mucus barrier degradation, host-bacterial contact, and inflammation.

Whether these mechanisms translate to the human situation and contribute to systemic inflammation that drives CMD development, remains unknown.

Mucus-resident gut bacteria are poorly reflected in fecal samples, resulting in a knowledge gap that I will address by combining my clinical gastroenterology background with 1) my expertise in state-of-the-art methods for mucus analysis, and 2) the front-edge methods for microbiome analysis that I learnt at the Broad Institute of MIT & Harvard.The overall hypothesis of this proposal is that disruption of gut mucosal host-microbe homeostasis promotes CMD development and partly mediates the detrimental effects of fiber deprivation.

Insights from the studies in this proposal may open up a novel research area in CMD, and inform future research into preventive microbiota-directed therapies to strengthen gut mucosal defenses.